FR2590484A1 - PHYSIOLOGICALLY ACCEPTABLE METAL COMPLEX SALTS USEFUL FOR NMR DIAGNOSIS - Google Patents

Abstract

Disclosed is a diagnostic agent comprising a complex salt. This salt contains an anion originating from a complexing acid, such as ethylenediaminetetraacetic acid, diethylene-triamine-pentacetic acid or trans 1,2-cyclohexylene diamine-tetraacetic acid, and one or more ions central elements of atomic numbers 21 to 29, 42, 44 or 57 to 83, and optionally one or more cations of inorganic or organic bases or of amino acids. This diagnostic agent optionally contains customary additives and is presented in the form of an aqueous solution or suspension. It can be used, for example, for X-ray radiography, for ultrasonic ultrasound or for zeugmatography.

Description

The invention relates to a diagnostic agent

  containing at least one physiologically acceptable complex salt

table.

  In medicine, for some time now, complex complexes or complex salts have been used,

  for the administration of poorly soluble ions (eg

  full of iron ions) and as antidotes (it is preferable to use calcium or zinc complexes) to detoxify heavy metals or their radioactive isotopes

  in case of accidental administration thereof.

  That being so, the present inventors have found

  certain complex salts, acceptable from the point of view of

  siological, derived from the anion of a complexing acid and

  of one or more central ions of atomic number elements

  21 to 29, 43, 44 or 57 to 83 and optionally one or more cations, physiologically harmless, from

  mineral and / or organic bases or amino acids,

  come remarkably well for the preparation of diagnostic agents for use in NMR (zeugmatography), x-ray (x-ray) or

  ultrasound (ultrasound or ultrasonography).

  The subject of the present invention is therefore an agent

  diagnostic system containing at least one complex salt, which is

  Physiologically, derived from the anion of a complexing acid and a central ion (there may also be several) from an element whose atomic number is one of the following: 21 at 29, 42, 44 and 57 to 83, and optionally a cation physiologically

  harmless (there may also be several)

  with a mineral base and / or an organic base or a

  amino acid, optionally with the usual additives

  used in pharmacy, in the form of a solution or

  a suspension in an aqueous medium.

  For the applications for which the diagnostic agent according to the invention is intended, the element which is defined above by its atomic number and which forms the central ion or one of the central ions of the physiologically acceptable complex salt obviously does not need

to be radioactive.

  When the agent according to the invention is intended to be used for the diagnosis by NMR, the central ion of the complex salt must be paramagnetic. This is particularly the case for divalent and trivalent ions of atomic number elements 21 to 29, 42, 44 and 58 and 70. Suitable ions that may be mentioned include, for example, chromium (III) and manganese (II) ions, iron (III), iron (II). cobalt (II),

  of nickel (II), copper (II), praseodymium (III), neo

  dyme (III), samarium (III) and ytterbium (III). We appreciate

  especially because they have a magnetic moment

  that very intense, the ions of gadolinium (III), terbium (III),

  of dysprosium (III), holmium (III) and erbium (III).

  When the product according to the invention is to be used for X-ray diagnosis, it is necessary for the central ion to be derived from an element of relatively high atomic number if it is desired to attain a sufficient absorption of X-rays. will be able to use, as well as the presents

  inventors have found, diagnostic agents that

  hold a complex salt that is physiologically acceptable

  logic, whose central ion is that of one of the atomic number elements between 57 and 83; for example, the lanthanum ion (III), the lanthanide series ions mentioned above, the gold ion (III), the lead ion (II) ) or, especially, the bismuth ion (III).

  For ultrasound application (ultrasonogra-

  phie) are suitable as well as the agents according to the invention.

  which are intended for diagnosis by NMR only those intended for X-ray diagnosis.

  Suitable complexing acids are, in particular,

  those ordinarily used for the complexion of

  central ions mentioned above. Suitable complexing acids include, for example, compounds of this type which contain from 3 to 12, preferably from 3 to 8, radicals of methylenephosphonic acid, methylene-carbohydroxamic acid, carboxyethylidene or, especially,

  carboxymethylenes, one, two or three of these different

  dicals being fixed at a nitrogen atom supporting the formation of the complex. When three of the acid radicals are attached to a nitrogen atom, we are dealing with the complexing acids which are at the base of the complex salts corresponding to the general formula II:

N (CH2X) 3 I)

  in which X represents -COOY, -PO3HY or -CONHOY radicals in which Y represents a hydrogen atom, an ionic equivalent of metal and / or a cation, devoid of physiological inconveniences, originating from a mineral or organic base or an amino acid, with the condition

  that at least two of the substituents Y represent

  ionic equivalents of metals with atomic numbers 21 to 29, 42, 44 or 57 to 83. If there are only one or two of these

  acid radicals on a nitrogen atom then this one is re-

  linked to another nitrogen atom via a radi-

  optionally substituted ethylene glycol-or via 1 to 4 ethylenic units, each of which is attached to the following by a nitrogen, oxygen or sulfur atom supporting the formation of the complex. As complexing acids of this latter type, those which correspond to the general formula I are very much appreciated:

X-CH 2 N CH 2 -X (I)

2N-A-N 2

V-CHR = CHR -V

  in which X has the meaning just given,

  A represents a radical corresponding to one of the

mules:

-CHR zCHR3- '-CH2 2 -H' (ZCH2 CH2) n

N (CH2X) 2 CH2-CH2-N (CH2X) 2

  -CH22 -CH -CH 2- and _CH2-CH -CH 2 2

and -CH2-CH2-N-CH2-CH2-

CH2-CH-CH2 -H-H-

  in which X has the meaning previously given,

  R1 represents a hydrogen atom or a radical

  methyl cal, R2 and R3 together form a trimethylene radical or a tetramethylene radical or represent

  each one a hydrogen atom, a radical al-

  kyle, a phenyl radical or a radical

  benzyl callus, R2 may also represent a hydrogen atom and R3 a radical: - (CH2) p-C6H4-W-protein

  where p is 0 or 1, W represents

  is a radical -NN-, -NHCOCH2- or -NHCS-, and "-protein" denotes a protein radical, m denotes a number equal to 1, 2 or 3, Z represents an oxygen atom, a Sulfur atom or one of the radicals:

-_ NCH 2X

  and NCH 2 CH 2 O 4 where X has the meaning given above and R 4 represents a lower alkyl radical, and V has one of the meanings which have been given

  above for X or represents one of the radi-

  cals: -CH2OH, -CONH (CH2) nX and -COB in which

  X has the meaning previously given, B represents

  a radical of protein or lipid and n denotes a number from 1 to 12, or in the case where R1, R2 and R3 each represent a hydrogen atom, the two V symbols together form a radical:

CH2X CH2X

2 (CH 2) w-N-CH-CH 2 -N- (CH 2)

- (CH 2) n-CH 2 CH 2 -N- (CH 2) w-

  in which X has the previously given meaning and w denotes a number equal to 1, 2 or 3,

  with the proviso that at least two of the substituents Y represent

  They are equivalents of metals with atomic numbers 21 to 29, 42, 44 or 57 to 83. The complexing acids may be conjugated, in the form of conjugates, with biomolecules known to be particularly concentrated in the organ or the organ part to be studied. Such biomolecules are for example hormones, such as insulin, prostaglandins, steroid hormones, amino sugars, peptides, proteins or lipids. Special mention should be made of albumin-conjugated conjugates, such as human serum albumin, antibodies, for example monoclonal antibodies specific for antigens associated with

  tumors, or antimyosin. Diagnostic agents that

  Such conjugates are suitable, for example, for the diagnosis of tumor and infarction. For exams

  on the liver, for example, conjugates or

  inclusion salts formed with liposomes, which are involved for example in the form of unilamellar vesicles

  or multilamellar phosphatidylcholine or cholesterol.

  The formation of the conjugate involves either a radical car-

  complexing acid boxy, that is, in the case of proteins or peptides, also a radical- (CH 2) -C 6 H 4 -W- as defined above with respect to the formula I. Ru course of the

  formation of a conjugate between, on the one hand, a

  plexant and, on the other hand, a protein, a peptide or a

  It can sometimes happen that many of the acid radicals bind to the macromolecular biomolecule. In this case, each of the complexing acid radicals may carry a central ion. When the complexing acids are not linked to

  biomolecules they eventually carry two central ions

  traux, but more particularly a central ion.

  Among the complex salts of general formula I, for example, those which have the general formula Ia are most preferred:

X-CH2 CH 2 X

N-CHR_2-CHR 3 N

  V-CHR1 lR (Ia) 1 CHRi.V'V wherein X, V, R1, R2 and R3 oht the meanings which

  have been given above about formulas I and II.

  To prepare complex salts of formula

  In general, it is possible to consider, inter alia,

  following plexants: ethylenediaminetetraacetic acid, ethylenediaminetetrahydroxamic acid, trans-cyclohexylenediaminetetraacetic acid, 2,3-butylenediaminetetracetic acid DL, acid 1,2-butylenediaminetetracetic DL, 1,2-propylenediamine-1,2-tetracetic acid, 1,2-diphenylethylene-diamine-tetracetic acid, ethylene-dinitrilotetrakis (methanphosphonic acid) ) and

  N- (2-hydroxyethyl) ethylene-diamine triacetic acid.

  Other complexing salts of general formula

  I are also of great interest, for example those which correspond to the general formula Ib: ## STR5 ## which X, V, Z, R1 and m have the meanings given above. When Z represents an oxygen atom or a sulfur atom it is preferable that m is

equal to 1 or 2.

  In order to prepare the complex salts of general formula Ib, it is possible to use, inter alia, the following complexing acids: diethylene-triamine-pentaacetic acid, triethylene tetramine hexacetic acid, tetraethylene pentamine-heptacetic acid,

  dioxo-13,23 tris- (carboxymethyl) -15,18,21 penta-

  aza-12,15,18,21,24 pentatriacontane-dioic acid, bis- (1-carboxy-ethyl-3,9-triaza-3,6,9 undecane-diol,

  diethylenetriamine pentakis (methylenephosphoric acid)

nique), -

  1,1,10-dioxa-1,4-decane-tetracetic-1,1,10,10-diaza acid and

  diaza-l, 10,10-dithia-4,7-decane-tetraacetic-1,1,10,10-acid.

  Among the complex salts of general formula I which are particularly suitable are those which correspond to the general formula Ic:

X-CH2. CH2-X

N-CH2-CH2 N

CH CH

2 '2 (Ic),

(CH 2) (CH 2)

N-CH2-CH2-N \

X-CH2 CH2 X

  where X and w have the meanings that have been given

  For the preparation of the complex salts of the general formula Ic, it is possible to use as complexing acids between

  other, 1,4,8,11-tetra-1,4-cyclotetradecane-tetraacetic acid

  tetra-aza-1,4,7,10-cyclododecane-

  tetra. As other complexing acids suitable for the preparation of complex salts of general formula I

  for example, tris-Lbis- (carboxymethyl) amino-

  1,2,3 propane and nitrilo-tris- (ethylene-nitrilo) acid -

  hexacétique. As an example of a complexing acid for the preparation

  paration of complex salts of general formula II

nitrilotriacetic acid.

  When the acidic hydrogen atoms of

  the complexing acid are not all replaced by the central ion

  tral or the central ions it is good, to increase the

  solubility of the complex salt, to replace the hydrogen atoms

  The remaining genes are physiologically harmless cations from inorganic and / or organic bases or amino acids. For example, as mineral cations, those of lithium, potassium and especially sodium, as

  organic bases, those of primary amines, sec-

  dary or tertiary such as ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine

  and, especially, N-methylglucamine, and, as amino cations,

  acids, those of lysine, arginine or ornithine.

  The complexing acids which are necessary for the product (contrast agent) according to the invention are

  known or can be prepared in a known manner.

  Thus, dioxo-13,23 tris

  (carboxymethyl) -15,18, 21 penta-aza-12,15,18, 21,24 penta

  triacontane-dioic is prepared by the following method, which is an improvement on that proposed by R. A. Bulman et al. in Naturwissenschaften 68, (1981) 483:

  17.85 g (ie 50 millimoles) of bis (dioxo) acid are

  2,6-morpholino) -1,5-azapan-3-pentane-3-acetic acid suspended in 400 ml of anhydrous dimethylformamide and, after adding

  20.13 g (ie 100 millimoles) of 11-amino-undecanol

  that is heated for 6 hours at 700C. The clear solution is concentrated under reduced pressure. The residue is stirred

  oily yellow, at room temperature, with 500 ml of water.

  A voluminous solid body, almost white precipitates then; it is separated by spinning and washed several times with water. To purify it further we introduce the product

  obtained in 200 ml of acetone and stirred for 30 minutes.

  at room temperature. After spinning and drying

  at 50 ° C. under reduced pressure, 36.9 g (

  97% of the theoretical amount) of a white powder

at 134-138 C.

  The conjugation of the complexing acids with biomolecules is also carried out by known methods, for example by reaction of nucleophilic radicals of the biomolecule (such as amino, hydroxy, thio or

  imidazolyl) with an activated derivative of the complexing acid.

  The activated derivatives of the complexing acids will be, for example, chlorides of acids, anhydrides

  acids, activated esters, nitrites or isothiolines.

  cyanate. Conversely, it is also possible to do

  react an activated biomolecule with the complexing acid.

  Substituents of structure -C6H4N2 + or -C6H4NHCOCH2Halogen are also suitable for conjugation

with proteins.

  The preparation of the complex salts is also partly known or can be carried out in a known manner. For example, it is dissolved or suspended in water and / or in a lower alcohol (such as methanol,

  ethanol or isopropanol) the metal oxide or a metal salt

  (eg nitrate, chloride or sulphate) of atomic number element 21 to 29, 42, 44 or

  57 to 83, a solution or suspension of the quanti-

  equivalent of the complexing acid in water and / or a lower alcohol, and stirring, if necessary by slightly raising the temperature or heating to

  boiling point until the reaction is complete.

  undermined. When the complex salt formed is insoluble in the solvent used it is isolated by filtration. If it is soluble it can be isolated by evaporating the solution to dryness, by

  example by spray drying.

  When there are still acid radicals in

  the complex salt obtained it is often advantageous to transform

  sea this complex acidic salt, by means of mineral bases and / or

  organic or amino acids that form physiological cations.

  logically harmless, neutral complex salts and iso-

  ler these. In many cases we can not do otherwise

  because the dissociation of the complex salt is reduced by the de-

  pH to neutrality to such an extent that it is generally possible to isolate well-defined products or

less to purify them.

  It is good to use organic bases or basic amino acids for this neutralization, but this can also be carried out with advantage using mineral bases derived from sodium, potassium

  or lithium (hydroxides, carbonates or hydrogen carbonates).

  In order to prepare the neutral salts, it is possible, for example, to add to the acidic complex salts, in aqueous solution or suspension, an amount of the desired base sufficient for the point of neutrality to be reached. The solution obtained can then be concentrated to dryness under reduced pressure. It is often advantageous to precipitate the neutral salts formed by adding solvents that are miscible with water, such as lower alcohols (methanol, ethanol, isopropanol, etc.), lower ketones (acetone, etc.), polar ethers (tetrahydrofuran, dioxane, dimethoxy-i, 2

  ethane etc ...), which makes it possible to obtain crystal products

  are easy to isolate and purify themselves well. It has been found that it is particularly advantageous to add the desired base to the reaction mixture already during the course of the

  formation of the complex and thereby save an operational step

tory.

  When the acidic complex salts contain

  Several free acid radicals are often recommended

  to prepare neutral mixed salts which contain, as a con-

  ions, both mineral cations and cations

  organic, without physiological disadvantages. For this-

  for example, the complexing acid, in suspension or aqueous solution, can be reacted with the oxide or a salt of the element providing the central ion and with half of the

  amount necessary for the neutralization of an organic base

  Then, isolate the complex salt formed, then, if desired, purify it and then, to neutralize it completely, add the required amount of a mineral base. The basics

  can also be added in the reverse order.

  The preparation of the diagnostic agents according to the invention is also carried out in a known manner. For example we suspend or dissolve

  complex salts in an aqueous medium, optionally in addition to

  substances taken from those commonly used

  pharmacy and then sterilize the solution or

  suspension. Substances that can be added (addi-

  Examples are physiologically safe buffers (such as tromethamine hydrochloride), small additional amounts of complexing agents (such as diethylenetriamine pentaacetic acid) or, if necessary, electrolytes (such as chloride). sodium). The diagnostic agents according to the invention can even be prepared, in principle, without the complex salts being isolated. In any case, care should be taken with particular care that the formation of the chelate takes place in such a way that the salts and saline solutions in accordance with the invention are practically free of uncomplexed toxic metal ions. This can be done for example by means of colored indicators, such as orange

  xylenol, by control titrations during the manufacture of

  cation. The invention therefore also relates to processes for preparing the complex compound and its salts. A

  purification of the isolated complex salt may constitute a

sure of ultimate security.

  If one wishes to have, for the administration

  by oral route or for other applications,

  suspensions of complex salts in water or in a solution

  physiological salt solution is mixed a poorly soluble complex salt with one or more of the adjuvants and / or surfactants and / or saporific (taste correctors) commonly used

in pharmacy.

  The diagnostic agents according to the invention preferably contain from 1 micromoles to 1 mole of the complex salt per liter and are generally administered in amounts corresponding to doses of

  0.001 to 5 millimoles per kg of body weight. They are

  to the oral route and, above all, to the parenteral route.

  The products (the forms of the invention) satisfy the multiples

  conditions imposed on a contrast agent intended to

  born with NMR tomography. Thus they are remarkably suitable after being administered orally or parenterally, because they increase the intensity of the signal, to improve the wealth of information provided by the zeugmatographic image. In addition they have a

  efficiency so great that they can be used for

  extremely small, the quantity of foreign bodies introduced

  Thus, the compounds in the organism are thus reduced to a minimum, and they have the good tolerance which is necessary to maintain the non-aggressive nature of the examination. For example, the compounds mentioned in J. Comput. Tomography 5.6: 543-46 (1981), in Radiology 144, 343 (1982) and in the special drug patent N 484 M (1960) are too toxic. The products according to the invention having a good solubility in water can be put in the form of very concentrated solutions, which makes it possible to maintain the volemia within acceptable limits and to compensate for the dilution caused by the body fluid, diagnostic agents for NMR to have a solubility in water 100 to 1000 times higher than that required for NMR spectroscopy. In addition, the products according to the invention not only have a high stability in vitro but also excellent stability in vivo, so that release or exchange of the ions, toxic by themselves, not covalently bound in the complexes It was extremely slow in the 24-hour period as pharmacological research showed the complete excretion of the new contrast agents. Conjugates with proteins or antibodies that are used by

  example for the diagnosis of tumors provoke a

  signal at such a low dose that solutions can be

is lowered accordingly.

  The products according to the invention are remarkably well suited as contrast agents for X-ray radiography. In this connection, it should be pointed out that, when these products are used, no signs of the reactions of the cells are observed in biochemical and pharmacological researches. anaphylactic type which are known for contrast agents containing iodine. They are

  particularly interesting because of their good

  absorbent in the high voltage regions of

  tubes, for digital subtractior techniques.

  The products according to the invention, because they exert a favorable influence on the speed

  ultrasound, are also suitable as diagnostic agents for

  tic for ultrasound ultrasound.

  In contrast to conventional radiographic examination using X-ray opacifiers, the signal in NMR examination using paramagnetic contrast agents

  not linearly depending on the concentration

  cated. As verification research has shown,

  an increase in the administered dose does not necessarily lead to

  signal reinforcement and it can even happen,

  when the dose of paramagnetic contrast agent is high

  that the signal is canceled. This is why we can consider

  surprising that some pathological processes

  are visible only after application of doses of a highly paramagnetic contrast agent according to the invention more

  higher than those indicated in the European Patent

  71,564 (they can range from 0.001 millimole / kg to

  5 millimoles / kg). For example, one can not de-

  a malfunction of the blood

  in the region of an intracranial abscess after administering from 0.05 to 2.5 millimoles / kg, preferably from 0.1 to 0.5 millimole / kg, paramagnetic complex salts,

  such as the gadolinium / diethylenetriamine complex

* Pentacetic or manganese complex / cyclohexylene acid

  1,2-diaminetetracetic in the form of their very salts

  soluble in water. For a dose greater than 0.1 milli-

  mole / kg requires very concentrated solutions, the concentration of which can be up to 1 mole / liter and is preferably between 0.25 and 0.75 mole / liter, because

  only in this way can the stress due to

  lume and make it easier to handle the solution to be injected.

  Particularly low doses (inferred

  below 1 mg / kg) and, thus, less concentrated solutions (from 1 micromole / liter to 5 millimoles / liter) than those indicated in European Patent 71564 are necessary for diagnosis by organo-specific NMR, for example

  to detect tumors and myocardial infarction.

  The following examples illustrate the

this invention.

EXAMPLE 1

  Preparation of the gadolinoim-III / nitrilo-N, N, N-triacetic acid complex, C6H6GdNO6 The mixture is heated to 90 ° to 1000 ° C. while stirring.

  a suspension of 36.2 g (100 mmol) of

  linium (Gd203) and 38.2 g (300 mmol) of nitrilotriacetic acid

  tick in 1.2 liters of water and stir at this temperature

  for 48 hours. Then we eliminate the undisclosed materials

  activated carbon filtration and the filter is evaporated

  treated to dryness. The amorphous residue is pulverized. 60 g of product are collected, ie 87% of the theoretical amount. Melting point: 3000 C. Gadolinium content: calculated: 45.5%;

found: 44.9%.

  Iron-IIi complex of nitrilo-N, N, N-acid

  triacetic is obtained by means of ferric chloride FeCl3.

EXAMPLE 2

  Preparation of the di-sodium salt of the complex of

  gadolinium-III dioxo-13,23 tris

  (carboxymethyl) -15,18,21 penta-aza-12,15,18,21,24 pentatriacontanedioque, C36H60 GdN5012. 2 Na is suspended in 400 ml of water

  2 g (20 mmol) of dioxo-13,23 tris- (carboxymethyl) -

  , 18,21 penta-aza-12,15,18,21,24 pentatriacontane-diol and heated to 95 C. 7.43 g (20 mmol) of gadolinium chloride-III hexahydrate dissolved in 60 ml of water. The mixture is kept at this temperature for 2 hours, then, to neutralize the

  hydrogen chloride formed, 60 ml of a solution of

1N sodium hydroxide.

  When the reaction is complete (test with xylenol orange), the precipitate formed is filtered off and washed with water until it is free of chlorine. 17.60 g (96% of the theoretical amount) of a white, insoluble powder are collected

  in water, which melts at 290 - 292 C.

  Gadolinium-III complex of dioxo-13,23 acid

  tris (carboxymethyl) -15,18,21 penta-aza-12,15,18,21,24 pentatrium-

  contane-diolque. Analysis: (Calculated) C 47.30 H 6.84 N 7.66 Gd 17.20

  (Found) c 47.13 H 6.83 N 7.60 Gd 17.06.

  14.6 g (16 mmol) of the gadolinium-III complex thus obtained are suspended in 200 ml of water and 31.4 ml of a 1N solution of hydroxide are added dropwise.

  sodium. After one hour we obtain a solution

  which is filtered and then concentrated under

  pick. After drying at 80 ° C. under reduced pressure, 13.2 g (87% of the theoretical amount) of a white powder are obtained.

  very soluble in water, melting at 279 - 285 ° C.

  Analysis: (Calculated) C 45.13 H 6.31 N 7.31 Gd 16.41 Na 4.80

  (Found) C 45.20 H 6.12 N 7.28 Gd 16.26 Na 4.75.

  By operating in a similar way but using

  N-methylglucamine instead of sodium hydroxide solution gives the:

  ] i-N-methylglucamine salt of the gadolinic complex

  nium-III of dioxo-13,23 tris- (carboxymethyl) -

  , 18,21 penta-aza-12,15,18,21,24 pentatriacontane-

diolque, C5 H 96GdN 02

96 7 22V

EXAMPLE 3

  Preparation of the seldi-sodium of the complex of

  gadolinium-III bis (1-carboxyethyl) acid

  3.9 carboxymethyl-6-triaza-3,6,9 undecanediol, C16H22GdN301.2 Na. Suspended in 250 ml of water 36.2 g

  (0.1 mol) of gadolinium-III oxide and 84.2 g (0.2 mol) of

  bis- (carboxy-1-ethyl) -3,9 carboxymethyl-6-triaza-3,6,9 undecanedioic acid and heated at reflux for one hour. A small amount of undissolved material is removed by filtration and the solution is concentrated to dryness under reduced pressure. The residue is pulverized and dried at 60 ° C.

  reduced pressure. 112.8 g (98% of the

  theory) of the chelate in the form of a white powder.

  Anal. C16H24GdN3O10 (Calcd): C 33, 39 H 4.20 Gd 27.32 N, 7.30

  (Found): C 33.25 H 4.49 Gd 27.42 N 7.21.

  57.6 g (0.1 mol) of the chelate are introduced into a solution of 0.1 mol of sodium hydroxide in 100 ml of water. The pH of the solution is adjusted to 7.5 by adding an additional 0.1 mol of sodium hydroxide powder, the solution is heated to boiling and ethanol is added dropwise until persistence. trouble appeared. After having stirred for several hours on the

  ice bath, the product which crystallizes is separated by spinning.

  washed, washed with ethanol and dried under

  reduced. We obtain, with a quantitative yield, the

  di-sodium salt in the form of a white powder.

  Analysis: (Calculated) C 31.02 H 3.58 Gd 25.38 N 6.78

  (Found) C 31.10 H 3.71 Gd 25.50 N 6.61.

EXAMPLE 4

  Preparation of morpholine di-salt of the gadolinium-III complex of bis- (carboxy-1) acid

  ethyl) -3.9 carboxymethyl-6-triaza-3,6,9 undec

  cane-dioic, C24H42GdN5012. 17.4 g (0.2 mol) of morpholine are dissolved

  in 50 ml of water. 42.1 g (0.1 mol) of

  (1-carboxy-ethyl) -3,9-carboxymethyl-6-triaza-3,6,9 undecane

  then 18.2 g (0.05 mol) of gadolinium-III oxide and the whole is kept under reflux until a clear solution is formed. Acetone is then added dropwise until persistence of the haze appears. After waving for several hours on the ice bath one separates

  by spinning the crystallized product, wash it with a-

  ketone and dried under reduced pressure. We get, with

  a quantitative yield, morpholine di-salt in the form of

me of a white powder.

  Analysis: (Calculated) C 38.44 H 5.65 Gd 20.97 N 9.34

  (Found) C 38.31 H 5.72 Gd 20.76 N 9.32.

EXAMPLE 5

  Preparation of N-methylglucamine di-salt from

  gadolinium-III complex of diethylene

  triamine-N, N, N ', N ", N" -pentacetic, C28H54GdN5O20.

  39.3 g are suspended in 200 ml of water

  (100 mmol) of diethylenetriamine-N, N, N ', N ", N" -penta-

  and 19.5 g (100 mmol) of N-methylglucamine were added.

  18.12 g (50 mmol) of Gadolinium III Gd203 oxide are then introduced in portions and the suspension obtained is heated.

  at 95 C. After about 1 hour, an additional 19.5 g is added.

  (100 mmol) of N-methylglucamine and, after heating

  for another 2 hours, a clear solution is obtained.

  When the reaction is complete (checking with xylenol orange) a small amount of undissolved material is removed by filtration and the filtrate is concentrated to dryness under reduced pressure. The residue is redissolved in 100 ml of water and the solution is added with stirring into 250 ml of ethanol. After cooling for several hours, the product which crystallized was filtered off with suction, washed with cold ethanol and dried at 60 ° C. under reduced pressure. We obtain 92.7 g (99% of the theoretical amount) of a white powder which does not

  not a characteristic melting point.

  Analysis: (Calculated) C 35.85 H 5.80 N 7.47 Gd 16.77

  (Found) C 35.50 H 5.72 N 7.20 Gd 16.54.

  To purify the complex salt one can, instead

  ethanol, use acetone, propanol or iso-

  propanol. By operating in a similar way we obtain:

  with dysprosium-III Dy203 oxide.

  the di-salt of N-methylglucamine from the dyspro-

  sium-III of diethylenetriamine-N, N, N ', N ", N" -

  pentacetic acid, C28H54DyN5020; with lanthanum-III oxide La203:

  N-methylglucamine di-salt of the lanthan

  ne-III diethylenetriamine-N, N, N ', N ", N" -

  pentacetic acid, C28H54LaN5020; with ytterbium-III oxide Yb203:

  N-methylglucamine di-salt of the ytter-

  bium-III diethylenetriamine-N, N, N ', N ", N" -

  pentacetic acid, C28H54YbN5020; with Samarium-IIr oxide Sm203:

  the di-salt of N-methylglucamine from the sama-

  diethylenetriamine-N, NN ', N ", N" -

  pentaacetic acid, C28H54SmN5020; with holmium-III oxide Ho203: N-methylglucamide di-salt of the holmium-III complex

  diethylenetriamine-N, N, N ', N ", N" -pentacid-

  tick, C28H54HON5020; with Bismuth-III Bi203 oxide: N-methylglucamine di-salt of the bismuth-III complex

  diethylenetriamine-N, N, N ', N ", N" -pentacid-

  tick, C28H54BiN5020; with gadolinium-III Gd203 oxide:

  the tri-salt of N-methylglucamine of the gadolinic complex

  nium-III triethylene tetramine-N, N, N ', N'N, N "-

hexacetic acid, C39H78GdN7027.

  It is also obtained: with the holmium-III oxide Ho 2 O 3 and ethanolamine instead of N-methylglucamine: the di-ethanolamine diethyl salt of the diethylene triamine-3 N, N, N ', N ", N" -pentacetic, C18H34HoN5O12; with gadolinium-III Gd203 oxide and lysine instead of N-methylglucamine: lysine di-salt of the gadolinium III complex of diethylene-triamine-N, N, N ', N ", N" -pentacetic acid, C26H48GdN7014. By using diethanolamine, the diethanolamine di-salt of the holmium-III complex of

  diethylenetriaminepentaacetic acid, C22H42HoN5014.

  The salts are obtained in the form of powders

  bleache having no characteristic melting point.

They are very soluble in water.

EXAMPLE 6

  Preparation of the di-sodium salt of the complex of

  gadoliniumqII of diethylene triamine

  N, N, N ', N ", N" -pentaacetic, C14H18GdN3010.2 Na. 18.2 g (0.05 mol) of gadolinium-III oxide and 39.3 g are suspended in 110 ml of water. g (0.1 mol) diethylenetriaminepentacetic acid and refluxed for 1 hour. The clear solution is cooled and

  its pH is raised to 7.5 by the addition of about 80 ml of a solution.

  pentanormal sodium hydroxide. We heat up again

  to boiling and 250 ml of ethanol are added dropwise.

  After stirring for several hours on the ice-bath, the product which crystallized was filtered off with suction, washed with ice-cold ethanol and dried at 60.degree. C. under reduced pressure. We obtain, with a quantitative yield, a white powder which has not always

  not melted when its temperature was raised to 300C.

  Analysis: (Calculated) C 28.43 H 3.07 N 7.10 Gd 26.58

  (Found) C 28.35 N 2.95 N 7.05 Gd 26.37.

  By operating in a similar manner, the following is obtained with the dysprosium-III oxide Dy 2 O 3: the di-sodium salt of the dysprosium-III complex of diethylenetriamine-N, N, N ', N ", N" - pentacetic acid, C14H18DyN3010.2 Na; with the lanthanum-III oxide La203: the di-sodium salt of the lanthanum-III complex of diethylenetriamine-N, N, N ', N ", N # -pentaacetic acid, C14H18LaN3010.2Na; holmium-III oxide Ho203 the di-sodium salt of the diethylenetriamine-N, N ", N", N ", N" pentaacetate diethylenetriamine-III complex, C14H18HoN3010.2 Na; of Ytterbium-III Yb203: the di-sodium salt of the ytterbium-III complex of diethylenetriamineN, N, N ', N ", N" -pentacetic acid, C14H18YbN3010.2Na; samariumIII Sm203: the di-sodium salt of the samarium-III complex of diethylenetriamine-N, N, N ', N ", N" -pentacetic acid, C14H 18SmN3010.2 Na, with erbium oxide -III Eb203: the di-sodium salt of the erbium-III complex of diethylenetriamine-N, N, N ', N ", N" -pentacetic acid, C14H18EbN30102 Na;

1418 3 10 '

  with gadolinium-III Gd203 oxide: the sodium salt of the gadolinium-III di-complex of

  tetraethylene pentamine-N, N, N ', N ", N", N'v, N'-

heptacetic acid, C22H30Gd2N5014 Na.

  These salts are obtained in the form of white powders having no characteristic melting point

  and they are very soluble in water.

EXAMPLE 7

  Preparation of the N-methylglucamine salt of the complex

  iron-III diethylenetriamine-penta

C21H37FeN4015.

  35.40 g (90 mmol) of diethylene

  triamine pentacetic suspension in 100 ml of water and 24.3 g (90 mmol) of ferric chloride hexahydrate (FeC13.6 H20) dissolved in 100 ml of water. It is heated to 95 ° C

  the suspension, which is dark brown at first. At the end of

  its color changes to pale yellow. 270 ml of a 1N solution of sodium hydroxide are added to neutralize the hydrogen chloride formed and heated at 95 ° C. for a further 3 hours. The light yellow precipitate formed is filtered off with suction, washed with water to remove the chloride ion and dried at 60 ° C. under reduced pressure. 17.85 g (45% of the theoretical amount) of a light yellow powder are obtained,

  the melting point is greater than 300 C.

  17.85 g (40 mmol) of the iron-III complex thus obtained are placed in 200 ml of water and 7.8 g (40 mmol) of N-methylglucamine in the solid state are added in portions; . It is heated at 50 ° C. for approximately 3 hours. A clear red brown solution is then obtained, filtered and concentrated to dryness under reduced pressure. The residue is dried at 50 ° C. under reduced pressure. We obtain 24.3 g (95% of the

  theoretical amount) of a reddish-brown powder that melts at 131-133 C.

  Analysis: (Calculated) C 39.82 H 5.89 N 8.85 Fe 8.81

  (Found) C 39.70 H 6.00 N 8.65 Fe 9.01.

  If a solution of sodium hydroxide is used instead of the organic base, the following are obtained: EI salt of the iron-III complex of ethylene-diamine-tetracetic acid, ClOH 2FeN2O8.Na, the sodium salt of the complex of iron-III of trans-cyclohexylenediamine-1,2-tetracetic acid, C14H18FeN208.Na, the di-sodium salt of the iron-III complex of diethylene-trinitrilo-penta- (methanphosphonic) acid, C9H23FeN3015P5 .2 Na, the sodium salt of iron-III complex of diaza-l, dioxa-4,7-decane-tetracetic acid-1,1,10,10, C14H20FeN2010.Na and the sodium salt of the iron complex -III acid

  ethylene diamine tetra acethydroxamic acid, C10H16 FeN608.Na.

  With N-methylglucamine, the following is obtained: N-methylglucamine di-salt of the iron-III complex of diethylenetriamine-N, N, N ', N ", N" -pentacetic acid, C28H54FeN5020 , the N-methylglucamine salt of the iron-III complex of cyclohexylenediamine-1,2-N, N, N ', N'tetriacetyl, C21H36FeN3013, the N-methylglucamine salt of the iron-III ethylenediamine-N, N, N ', N'-tetracetic acid, C17H30FeN3013, tri-salt of N-methyl-glucamine of the iron-III complex of triethylene-tetramine-N-acid N, N ", N", N ", N", N "- hexacetic, C39H78FeN7027A If diethanolamine is used instead of N-methylglucamine, the di-ethanolamine di-salt of the iron-III complex is obtained. diethylenetriamine-N, N, N ', N ", N" -pentaacetic acid, CH FeN O 22H42FeN5014

EXAMPLE 8

  Preparation of the N-methylglucamine salt of the complex

  of gadolinium-III of cyclohexylene-diamine

  1,2 N, N, N ', N'-tetracetic trans, C21H36GdN3013.

  In 150 ml of water is suspended 20.78 g

  (60 mmol) of cyclohexylenediamine-1,2 N, N, N ', N'-tetrasacral

  trans tick. After adding 11.7 g (60 mmol) of N-methyl-

  Glucamine gives an almost clear solution, to which is added 10.88 g (30 mmol) of gadolinium oxide (Gd203). A suspension is again obtained, which is heated at 95 ° C. for 6 hours. a small amount of

  undissolved material and the filtrate is concentrated to dryness.

  The residue is dried at 60 ° C. under reduced pressure and pulverized.

  Verise. We obtain 38.6 g (92% of the theoretical amount)

  a white powder that melts at 258-261 C.

  Analysis: (Calculated) C 36.25 H 5.22 N 6.04 Gd 22.60

  (Found) C 36.40 H 5.50 N 5.98 Gd 22.52.

  By operating in the same way but using

  sodium hydroxide solution instead of N-methyl-

  glucamine is obtained: the sodium salt of the gadolinium-III complex of cyclohexylene-diamine-1,2 N, N, N ', N'-tetracetic trans,

C14H18GdN208.Na.

  With chromium-III chromium hydroxide Cr (OH) 3

  precipitated one obtains: the sodium salt of the chromium-III complex of the acid

  ethylene diamine-N, N, N ', N'-tetractique, Co10H12CrN208.Na.

EXAMPLE 9

  Preparation of the sodium salt of the manganese complex

  II cyclohexylenediamine-1,2-N, N, N ', N'-

  trans tetracetic acid, C14H18MnN208.2 Na.

  34.6 g (100 mmol) of cyclohexylenediamine-1,2 N, N, N ', N'-trans-tetracetic acid are suspended in 100 ml of water, under nitrogen, and 11.5 g are added. g (100 mmol) of manganese carbonate II MnCO 3. The mixture is heated to 95 ° C. and 20 ml of normal sodium hydroxide solution are added dropwise. The clear solution is concentrated under pressure:

  reduced and the residue was dried at 60 ° C. under reduced pressure.

  40.8 g (92% of the theoretical amount) of a pink powder are obtained. Analysis: (Calculated) C 37.94 H 4.09 N 6.32 Mn 12.40

  (Found) C 37.78 H 4.12 N 6.20 Mn 12.31.

  Analogously, from copper-II carbonate: the di-sodium salt of the copper-II complex of trans-cyclohexylenediaminetetraacetic acid, C14H18CuN208.2Na; from cobalt-II carbonate: the di-sodium salt of the cobalt-II complex of trans-cyclohexylenediamine-1,2-tetracetic acid, C14H18CoN208.2 Na; from nickel-II carbonate: the di-sodium salt of the nickel-II complex of trans-cyclohexylenediamine-1,2-tetraacetic acid, C H NiN has 14H18NiN208ONa. Using N-methylglucamine instead of a sodium hydroxide solution, the following is obtained: N-methylglucamine di-salt of the manganese-II complex of cyclohexylene-diamine-1,2-tetracetic acid trans, C28H54MnN4O8; N-methylglucamine di-salt of the 2,3-butylene-diamine-2,3-tetracetic acid manganese-II complex, C26H52MnN4O8; N-methylglucamine di-salt of the manganese complex II of ethylene-diamine-N, N, N ', N'-tetracetic acid, C H MnNO0 24H48MnN4 18; N-methylglucamine di-salt of the manganese-II complex of 1,2-butylenediamine N, N, N ', N'-tetracetic acid DL, C26H52MnN4018; N-methylglucamine di-salt of the manganese-II complex of propyl-1,2-diamine N, N, N ', N'-tetracetic acid DL, C25H50MnN4018; N-methylglucamine trisel of the diethylene triaminepentaacetic acid mangane-II complex, C35H72MnN6025; with nickel-II NiCO3 carbonate: N-methyl-glucamine di-salt of the nickel-II complex of ethylene-diamine-N, N, N ', N'-tetracetic acid, C24H48NiN4018; with cobalt-II CoCO3 carbonate and ethanolamine: ethanolamine di-salt of the cobalt-II complex of ethylene-diamine-N, N, N ', N'-tetracetic acid, C14H28CoN4010; with copper carbonate-II CuCO3 and ethanolamine: the ethanolamine di-salt of the copper-II complex of ethylene-diamine-N, N, N ', N'-tetracetic acid, C14H28CuN4010; with manganese carbonate-II MnCO 3 and diethanolamine: tri-salt of diethanolamine of the manganese-II complex of diethylenetriamine, N, N ', N', N "-pentacetic acid, C26H54MnN6016; of manganese II MnCO3 and morpholine: the morpholine di-salt of the manganese-II complex

  ethylene-diamine-N, N, N ', N'-tetracetic acid,

C18H32MnN4010O

EXAMPLE 10

  N-methylglucamine salt of the gadolinium complex

  nium-III of ethylene-diamine-N, N, N ', N'-

Tetracetic acid, C17H30GdN3013.

  29.2 g (100 mmol) of ethylenediamine-N, N, N 'and N'-tetracetic acid are suspended in 100 ml of water and

  heated to 95 ° C. with 18.1 g (50 mmol) of gadolinium oxide.

  nium-III Gd203. During heating, 19.5 g (100 mmol) of N-methylglucamine are added in portions. After about 3 hours a clear solution is obtained, filtered and concentrated to dryness under reduced pressure. The residue is dried at 60 ° C. under reduced pressure. 61.3 g (95% of the theoretical amount) are collected of a white powder without a point of

characteristic fusion.

  Analysis: (Calculated) C 31.82 H 4.71 N 6.55 Gd 24.51

  Proved) C 31.65 H 4.59 N 6.52 Gd 24.56.

  By operating in a similar manner, Dys203-Dy203 oxide: the N-methylglucamine salt of the ethyl-diamine-N, N, N ', N'-tetraacetic acid dysprosylamine complex, C17H30DyN3013; Similarly, the N-methylglucamine salt of the gadolinium-III complex is prepared in the same way.

  1,100-dioxa-4,7-decane-tetraacetic acid

  1,1,10,10, C21H38GdN3015; N-methylglucamine salt of 1,2-diphenylethylenediamine tetracetic acid gadolinium-III complex, C29H38N3013Gd; with lead oxide-II PbO and sodium hydroxide: the di-sodium salt of the lead-II complex of ethylene-diaminetetraacetic acid, CloH12N2O8Pb.2 Na; with freshly precipitated chromium-III chromium (Cr (OH) 3 hydroxide: the sodium salt of the chromium-III complex of ethylene-diamine-tetracetic acid, ClOH12CrN208.Na, and likewise: the sodium salt of the complex of gadolinium-III of ethylene-diaminetetraethyldroxamic acid, ClOH16GdN608.Na and the sodium salt of the gadolinium-III complex of the acid

  ethylenediamine-N, N, N ', N'-tetracetic acid, Co10H12GdN208.Na.

EXAMPLE 11

  Preparation of the sodium salt of the gadolinic complex

  nium-III of tetra-aza-1,4,7,10-cyclododecane-

  N, N ', N ", N"' - tetracetic, C16H24GdN4O8.Na is suspended in 20 ml of water 4.0 g

  (10 mmol) 1,4-tetraazo-1,4,7,10-cyclododecane-N, N ', N ", N" -

  Tetracetic acid and 10 ml of a 1N solution of sodium hydroxide are added. 1.8 g (5 mmol) of gadolinium-III oxide is added

  Gd203 and the suspension is heated for 2 hours at 50 ° C.

  The clear solution is filtered and concentrated under reduced pressure. The residue is dried and pulverized. 5 g (95% of the theoretical amount) of a white powder are collected. Analysis: (Calculated) C 33.10 H 4.17 N 9.65 Gd 27.08

  ITreated) C 33.01 H 4.20 N 9.57 Gd 27.16.

  The following is analogously obtained: the N-methylglucamine salt of the gadolinium-III complex

  1,4,7,10-tetraaza-cyclododecane-N, N ', N ", N" -

  tetracetic acid, C23H42GdN5013 / and the sodium salt of the gadolinium III complex of the acid

  1,4,8,11-tetraazaba, cyclotetradecan-N, N ', N ", N"' -

tick, C18H28GdN408 Na.

EXAMPLE 12

  Preparation of N-methylglucamine tetraisal salt from

  gadolinium-III complex of ethylene

  dinitrilo-tetrakis- (methanphosphonic), C35H85GdN6032P4. The suspension is suspended in 150 ml of water 9.11 g

  (20 mmol) of ethylene dinitrilotetrakis (methane)

  phosphonic acid) and the pH is adjusted to 5 with the corresponding amount.

  of N-methylglucamine. 3.6 g (10 mmol) of gadolinium-III Gd203 oxide are added and the mixture is heated to 70 ° C. After about 1 hour a clear solution is obtained, to which is added the remaining amount of N-methyl- Glucamine base

  which is consumed in a total amount of 15.6 g (80 mmol).

  The solution is concentrated to dryness under reduced pressure and

  produced in 200 ml of acetonitrile the remaining gelatinous product.

  The mixture is stirred at 30 ° C. for about 20 hours and the fine precipitate obtained is filtered off with suction and dried at 40 ° C.

  reduced pressure, 23.4 g (85% of the theo-

  a white powder melting at 115-1180C.

  Analysis: (Calculated) C 29.78 H 6.25 N 6.13 P 9.04 Gd 11.47

  (Found) C 29.85 H 6.57 N 5.98 P 8.78 Gd 11.26.

We obtain the same way:

  hepta-salt of N-methyl-glucamine from the gadoid complex

  linium-III diethylenetriamine-N, N, N ', N ", N" -

  penta- (methanephosphonic), C58H144G LGdN10050P6; and, using sodium hydroxide solution instead of N-methylglucamine: the di-sodium salt of the gadolinium-III complex of diethylene trinitrilopenta- (methanphosphonic acid),

C9H23GdN3016P5.2 Na.

EXAMPLE 13

  Preparation of the di-sodium salt of the complex of

  manganese-II of ethylene-dinitrilotetrakis-

  (acethydroxamic acid), C10H16MnN608.2 Na.

  2.30 g are refluxed for 3 hours.

of manganese carbonate II and 7.05 g of ethylene

  dinitrilo-tetra- (acethydroxamic) in 18 ml of water. The pH is then adjusted to 7 by the addition of a dilute solution of sodium hydroxide and 40 ml of acetone are added dropwise. After stirring for several hours on an ice-bath, the crystalline product which has formed is filtered off with suction, washed with acetone and dried at 50 ° C. under reduced pressure. We obtain, with a quantitative yield,

  a dihydrate in the form of a white powder which melts

above 300 C.

Mn: (Calculated) 11.30

(Found) 11,12.

EXAMPLE 14

  Preparation of a solution of the mixed sodium salt

  and N-methylglucamine of the gadolinium-

  III diethylene triamine pentaacetic acid.

  a) Preparation of N-methylglucamine mono-salt

of the complex, C21H37GdN4015.

  195.2 g (1 mol) of N-methylglucamine are dissolved in 7 liters of water. 393.3 g (1 mole) of diethylenetriaminepentaacetic acid and 181.3 g (0.5 mole) of oxide are then added.

  gadolinium Gd203 and refluxed for 2 hours.

  After filtering the clear solution, dry it by pul-

  vérisation. A crystalline white powder is obtained which has a water content of 2.6%. This powder sintered at 133 ° C

and melts at 190 ° C by foaming.

Gd: (Calculated) 21.17

(Found) 21.34.

  b) Preparation of the neutral solution of the mixed salt.

  In 630 ml of water (that is to say for injection), 730.8 g (1 mole) of the salt obtained under a) are suspended and 40 g (1 mole) are added in portions. ) sodium hydroxide powder. The neutral solution is diluted to 1000 ml with p.i. water, introduced into flasks through a pyrogenic filter and sterilized while hot. This monomolar solution contains 753.8 g of the salt

mixed per liter.

EXAMPLE 15

  Preparation of a solution of N-methyl di-salt

  glucamine complex gadolinium-III diethylene triaminepentacetic acid. 535.0 g (730 mmol) of the salt described in Example 5 are suspended in 500 ml of water and the solution is passed over to pH 7.2 by the addition of 142.4 g (730 mmol) of water. mmol) of N-methylglucamine. We then extend to 1000 ml

  with water, the solution is blistered and

rilises hot.

EXAMPLE 16

  Preparation of a solution of di-sodium salt

  gadolinium-III complex of diethylene

  triamine pentaacetic. In 500 ml of p.i. water is suspended

  485.1 g (820 mmol) of the di-sodium salt obtained in Example 6.

  The mixture is then added to 1000 ml with p.i.

  solution in ampoules and heat sterilized.

EXAMPLE 17

  Preparation of a solution of the di-sodium salt of the dioxo-13,23 tris (carboxymethyl) -15,18,21 penta-aza-12,151 dioxoic acid complex; 18,21,24 pentatriacontane-dioic. In 500 ml of water 392.0 g (400 mmol) of the salt described in Example 2 are suspended and, by extending the suspension to 1000 ml with water p.i.

  turns into solution while warming slightly.

  The solution is placed in vials and sterilized hot.

EXAMPLE 18

  Preparation of a solution of the N-methyl salt

  glucamine of the gadolinium-III complex of the acid

  1,4,7,10-tetra-1,4-cyclododecane tetracetic acid.

  In 500 ml of p.i. water is suspended 370.9 g (500 mmol) of the salt mentioned in Example 11 and provoked

  the passage in solution extending to 1000 ml with water p.i.

  The solution is put in ampoules and sterilized while hot.

EXAMPLE 19

  Preparation of a solution of N-methyl di-salt

  Glucamine from the manganese-II complex of the acid

  cyclohexylene-diamine-1,2 transtetracetic trans.

  500 g of 395.9 g (500 mmol) of the salt mentioned in Example 9 are suspended in 500 ml of water. 1.3 g of ascorbic acid are added and the solution is passed over to 1000.degree. ml with water pi The solution is filtered under conditions of sterility and put in

bulbs.

EXAMPLE 20

  Preparation of a solution of N-methyl tri-salt

  Glucamine from the manganese-II complex of diethylene triaminepentacetic acid. In 600 ml of water, 514.4 g (500 mmol) of the salt mentioned in Example 9 are suspended in suspension. 1.3 g of ascorbic acid are added and the solution is passed through.

  extending to 1000 ml with water p.i.

  under sterile conditions and put it into

bulbs.

EXAMPLE 21

  Preparation of a solution of N-methyl di-salt

  Gludamine of iron-III complex of diethylene triaminepentacetic acid. In 40 ml of water, 44.6 g (0.11 mol) of the iron-III complex of diethylenic acid are suspended.

  triamine pentacetic which was obtained in Example 7. After adding 0.18 g of tromethamine hydrochloride and 39.1 g (0.2 mol) of N-methylglucamine a neutral solution is obtained, which is extended to 100 ml with water pi This is introduced

  solution in ampoules and heat sterilized.

EXAMPLE 22

  Preparation of a solution of the gadolinic complex

  nium-III nitrilo-triacetic acid.

  1.9 g (10 mmol) of nitrilo

  triacetic and 1.8 g (5 mmol) of gadolinium-III oxide in ml of water p.i. while heating. (n puts the solution in

  bulbs and is sterilized hot.

EXAMPLE 23

  Preparation of a solution of the N-methyl salt

  Glucamine of the gadolinium-III complex of ethylene diaminetetraacetic acid. 38.52 g (60 mmol) of the compound described in Example 10 are dissolved in 70 ml of water for injection. After adding 0.12 g of tromethamine, it is added to 100 ml with water. the solution in blisters and

sterilizes when hot.

EXAMPLE 24

  Preparation of a solution of N-methyl di-salt

  glucamine of the dysprosium-III complex of the acid

  diethylenetriamine pentaacetic.

  In 70 ml of water, 7 g (60 mmol) of the dysprosium-III complex of diethylenetriaminepentaacetic acid (water content: 8.0%) are suspended and the suspension is converted into solution. by raising its pH

  To 7.5 by addition of 21.2 g (120 mmol) of N-methylglucamine.

  Then dilute to 10 ml with water p.i.

  solution in ampoules and heat sterilized.

EXAMPLE 25

  Preparation of a solution of the N-methyl salt

  glucamine of the gadolinium-III complex of the acid

  trans-cyclohexylenediamine-1,2-tetracetic acid

  555.8 g (ie 0.8 mol) of the salt described in Example 8 are dissolved in a quantity of water p.i., such that the total evolution reaches 1000 ml. After filtration on a pyrogenic filter, the solution is put in ampoules and sterilized

hot.

EXAMPLE 26

  Preparation of a solution of the N-methyl salt

  glucamine of the ruthenium-III complex of the acid

  diaza-1,10 dithia-4,7 decane-tetraacetic-1,1,10,10.

  In 50 ml of water, 6 g (0.03 mol) of the ruthenium-III complex of diaza-1,10-dithia-4,7-decane-tetraacetic-1,1,10 acid are suspended, And the suspension is converted to a solution at pH 7.5 by the addition of 5.9 g (0.03 mol) of N-methylglucamine. It is extended to 1000 ml with water p. i., the solution is put in ampoules and sterilized while hot.

EXAMPLE 27

  Preparation of a solution of lysine di-salt

  gadolinium-III complex of diethylene

  triamine pentaacetic. In 500 ml of p.i. water, 273.8 g are suspended.

  (0.5 mol) of the gadolinium-III complex of diethylene

  triamine pentaacetic. 292.4 g (1 mol) of lysine are added,

  it is stirred for several hours while warming slightly

  Then, it is extended to 1000 ml with p.i.

  the solution in vials and heat sterilized.

EXAMPLE 28

  Preparation of a solution of N-methyl tri-salt

  glucamine of the molybdenum-VI complex of diethylene triaminepentacetic acid. In 50 ml of water, 18.8 g (0.28 mol) of the complex H 3 / -rMo 2 O 2 (OH) 4 C 14 H 23 N 3 O 10 7 are suspended and dissolved to neutrality by the addition of 16.4 g (0.84 mol). ) N-methylglucamine. 0.15 g of tromethamine is added, the mixture is diluted with water to 100 ml, the solution is subjected to

  sterile filtration and put in ampoules.

EXAMPLE 29

  Preparation of a solution of di-sodium salt

  manganese-II complex of ethylene-

  diamine tetraacetic acid. In 500 ml of p.i. water is suspended

  343.2 g (1 mol) of the manganese-II complex of ethyl

  diamine-tetracetic and dissolved to neutrality

  in portions, 80 g (2 mol) of sodium hydroxide. After adding 1.5 g of tromethamine, the solution is diluted to 1000 ml with water, placed in flasks and

sterilizes when hot.

io90484

EXAMPLE 30

  Preparation of a sodium salt solution

  iron-III complex of ethylene-diamine

  tetra. In 500 ml of p.i. water is suspended

  345.7 g (1 mol) of the iron-III complex of ethylene

  diamine-tetracetic and dissolved in neutral by adding, in portions, 40 g (1 mol) of sodium hydroxide. After adding 1.5 g of tromethamine, the solution is diluted to 1000 ml with p.i. water, placed in flasks and sterilized.

hot.

EXAMPLE 31

  Preparation of a solution of di-sodium salt

  iron-III complex of diethylene triamine

penta.

  In 500 ml of p.i. water is suspended

  334.6 g (0.75 mol) of the iron-III complex of diethylene

  triamine pentacetic and dissolved in neutral by adding, in portions, 60 g (1.5 mol) of sodium hydroxide. The solution is diluted to 1000 ml with p.i. water and placed in flasks.

and it is sterilized hot.

EXAMPLE 32

  Preparation of a sodium salt solution

  gadolinium-III complex of cyclic acid

  trans-hexylenediamine-1,2-tetracetic

  558.6 g (1 mol) of the salt mentioned in Example 8 are dissolved in a quantity of water p.i. such that the total volume reaches 1000 ml. We put the solution in bottles and we

sterilises it hot.

EXAMPLE 33

  Preparation of a solution of the N-methyl salt

  glucamine of the gadolinium-III complex of the acid

  1,2-diphenylethylene diamine tetracetic acid.

  In 600 ml of p.i. water is suspended

  396.9 g (500 mmol) of the salt described in Example 10 and

  form the suspension in solution by extending it to 1000 ml.

  The solution is introduced into ampoules and sterilized while hot.

EXAMPLE 34

  Preparation of a sodium salt solution

  iron-III complex of ethylene-diamine

  In 500 ml of water, 183.5 g (500 mmol) of the salt mentioned in Example 7 are suspended. 1.0 g of tromethamine is added, and the mixture is diluted to 1000 ml with water.

  the solution is put in ampoules and sterilized hot.

EXAMPLE 35

  Preparation of a solution of N-methyl di-salt

  Glucamine of lanthanum-III complex of diethylene triaminepentacetic acid. In 650 ml of water, 459.8 g (500 mmol) of the salt mentioned in Example 5 is suspended and is passed into solution by diluting to 1000 ml with water.

  The solution is put in ampoules and sterilized while hot.

EXAMPLE 36

  Preparation of a solution of N-methyl di-salt

  glucamine from the bismuth-III complex of the acid

  diethylene triamine pentaacetic.

  In 600 ml of water, 692.8 g (700 mmol) of the salt mentioned in Example 5 are suspended and, after

  having added 1.8 g of tromethamine, the

  pension in solution by extending it to 1000 ml with p.i.

  and heating slightly. We put the solution in ampoules

and it is sterilized hot.

EXAMPLE 37

  Preparation of a solution of N-methyl di-salt

  Glucamine of the acidic holmium-III complex

  diethylenetriamine pentaacetic.

  In 600 ml of p.i. water is suspended 662.0 g (700 mmol) of the salt mentioned in Example 5 and, after

  have added 1.8 g of tromethamine, the suspension is

  solution in solution to 1000 ml with water p.i.

  and heating slightly. We put the solution in ampoules

and heat sterilized.

EXAMPLE 38

  Preparation of a solution of N-methyl di-salt

  Glucamine of the ytterbium-III complex of diethylene triaminepentacetic acid. In 650 ml of water, 476.9 g (500 mmol) of the salt mentioned in Example 5 are suspended and, after the addition of 1.5 g of tromethamine,

  passage in solution extending to 1000 ml with p.i.

  The solution is put in ampoules and sterilized while hot.

EXAMPLE 39

  Preparation of a solution of di-sodium salt

  lanthanum-III complex of diethylene

triamine pentacétique.-

  In 650 ml of water, 573.2 g (1000 mmol) of the salt mentioned in Example 6 are suspended and, by extending to 1000 ml with water, the mixture is stirred into water.

  solution which has not yet been dissolved. We put the solution

  in ampoules and heat sterilized.

EXAMPLE 40

  Preparation of a solution of di-sodium salt

  Dysprosium-III complex of diethylene

  triamine pentaacetic. In 600 ml of water, 477.4 g (800 mmol) of the salt mentioned in Example 6 are suspended and the suspension is converted to a solution and diluted to 1000 ml.

  with water p.i The solution is put in ampoules and

rilises hot.

EXAMPLE 41

  Preparation of a solution of di-sodium salt

  holmium-III complex of diethylene

  triamine pentaacetic. In 500 ml of p.i. water is suspended

  299.6 g (500 mmol) of the salt mentioned in Example 6 and

  form the suspension in solution by extending it to 1000 ml with water p.i.The solution is put in ampoules and sterilized

hot.

EXAMPLE 42

  Preparation of a solution of di-sodium salt

  ytterbium-III complex of diethylene

  triamine pentaacetic. In 500 ml of water, 303.5 g (500 mmol) of the salt mentioned in Example 6 are suspended and the suspension is dissolved in solution with 1000 ml of water. put the solution in ampoules and sterilize

hot.

EXAMPLE 43

  Preparation of a solution of N-methyl tetrasalt

  Glucamine of the gadolinium-III complex of ethylene dinitrilotetrakis (methane phosphonic acid). In 500 ml of water, 137.1 g (100 mmol) of the salt mentioned in Example 12 are suspended and, after the addition of 0.8 g of tromethamine, the suspension is converted into solution and extended to 1000 ml with water pi On

  put the solution into ampoules and heat sterilize.

EXAMPLE 44

  Preparation of a solution of the gadolinic complex

  nium-III of N '- (2-hydroxyethyl) ethylene

  diamine-N, N, N'-triacetic acid. Dissolve in 6 ml of water p.i., while warming up,

  1.9 g (6.7 mmol) of N '- (2-hydroxyethyl) ethylene

  N, N, N'-triacetic diamine and 1.2 g (3.35 moles) of gadolinium-III oxide. We put the solution in ampoules and we sterilize

hot.

EXAMPLE 45

  Preparation of a solution of di-sodium salt

  Manganese-II complex of cyclohexylene acid

1,2-diaminetetraacetic trans.

  By operating under nitrogen, it is suspended in

  ml of water, 44.3 g (100 mmol) of the salt mentioned in the example

  9 and dissolve completely by diluting to 100 ml with water p.i The solution is put in ampoules and sterilized

hot.

EXAMPLE 46

  Preparation of a sodium salt solution

  gadolinium-III complex of tetrazaza acid

  1,4,8,11 cyclotetradecane-N, N ', N ", N"' - tetracetic.

  552.6 g (1 mol) of the salt mentioned in Example 11 are dissolved in a quantity of water p.i. such that the total volume reaches 1000 ml. We put the solution in bottles and we

sterilizes when hot.

EXAMPLE 47

  Preparation of a solution of di-sodium salt

  bismuth-III complex of diethylene

  triamine pentaacetic. 23.4 g (50 mmol) of bismuth-III oxide are suspended in 50 ml of water. After adding 39.3 g (100 mmol) of diethylenetriamine pentacetic acid and 4.0 g (50 mmol) of sodium hydroxide is refluxed until a clear solution is obtained. After having

  cooled the solution to room temperature or neutralized

  Add 4.0 g of sodium hydroxide and dilute to 100 ml with water p.i.

and heat sterilized.

EXAMPLE 48

  Preparation of a solution of di-sodium salt

  samarium-III complex of diethylene

triamine pentaacetic.

  It is dissolved in 65 ml of p.i.

  58.5 g (100 mmol) of the salt mentioned in Example 6. Spread with water-p.i. up to a total volume of 100 ml,

  we put in ampoules and sterilize hot.

EXAMPLE 49

  Preparation of a solution of N-methyl di-salt

  glucamine of the gadolinium-III complex of the acid

  dioxo-12,23 tris- (carboxymethyl) -15,18,21 penta

  aza-12,15,18,21,24 pentatriacontane-diol.

  In 250 ml of water, 4 g (100 mmol) of the salt mentioned in Example 2 are suspended and dissolved while heating. It is extended to 500 ml with p.i.

  the solution is put in ampoules and sterilized hot.

EXAMPLE 50

* Preparation of a solution of N-methyl di-salt

  glucamine from the manganese-II complex of ethylene-diaminetetraacetic acid. In 70 ml of water is dissolved 3.68 g (5 mmol) of the compound described in Example 9 and 0.4 g of sodium chloride is added to the solution. It is then added to 100 ml with water and the solution is introduced into ampoules through a sterile filter. The solution, which has a concentration of 280 milli-osmoles, is

isotonic to blood.

EXAMPLE 51

  Preparation of a di-sodium salt solution

  of the gadolinium-III complex of diethyl

  lene-trinitrilo-penta- (methane phosphonic acid).

  In 50 ml of water p.i is suspended 38.57 g (50 mmol) of the compound described in Example 12. It adjusts

  the pH of the suspension at 7.2 by addition of sodium hydroxide

  dium powder and extended to 100 ml with water p.i.

  The solution is put in ampoules and sterilized while hot.

EXAMPLE 52

  Preparation of a solution of tri-sodium salt

  Manganese-II complex of diethylene acid

  triamine pentaacetic. While operating under nitrogen, it is suspended

  in 100 ml of water, 39.3 g (100 mmol) of diethylene

  triamine pentacetic and 11.5 g of manganese-II carbonate are added. It is heated to 95 ° C. and 300 ml of a 1N solution of sodium hydroxide are added dropwise. The neutral solution is filtered under conditions of sterility and

put it in ampoules.

EXAMPLE 53

  Composition of a powder for the preparation of a suspension

  4,000 g of the gadolinium-III complex of diethylene

  triamine pentacetic (water content: 8.0%) 3.855 g sucrose

  0.100 g of a polymer which is a poly-oxyethylene-poly-

  oxypropylene and 0.005 g flavoring substance 8,000 g

EXAMPLE 54

  Preparation of a solution of the gadolinium-III complex of the diethylenetriamine-pentaacetic acid conjugate with albumin

human serum.

  To 20 ml of a solution of 3 mg of the protein in a 0.05 molar sodium hydrogencarbonate buffer

  (pH: 7-8) 10 mg of bis (2,6-dioxo-morpholino) acid are added

  1,5-aza-3-pentane-acetic acid-3. It is stirred for 30 minutes at room temperature and then dialyzed against a 0.3 molar sodium phosphate buffer. After that we add

  mg of gadolinium-III acetate and purified by chroma-

  gel graphography using a Sephadex G25 column.

  The fraction obtained is filtered under sterile conditions.

  and is introduced into multi-dose vials. By lyophilization, a dry composition is obtained which is well preserved. By operating in a similar manner but using the immunoglobulin, a solution of the corresponding conjugate-complex is obtained.

EXAMPLE 55

  Preparation of a solution of the gadolinium-III complex of the conjugate formed by diethylene triaminepentaacetic acid (DTPA) with a monoclonal antibody.

  To 20 μl of a solution of 0.3 mg of an anti-

  monoclonal body in 0.05 molar hydrogen

  sodium carbonate (pH: 7-8) 1 mg of a mixed anhydride is added

  DTPA (obtained for example from DTPA and chlorinated

  isobutyl formate) and is stirred for 30 minutes at room temperature.

  ambient temperature. Dialysis against a 0.3 mm buffer

  sodium phosphate and, at the anti-

  body obtained, 2 mg of the gadolinium-III complex of ethylene-diamine-tetra-acetic acid (EDTA) is added. After purification by gel chromatography with Sephadex G25, the solution is introduced into multidose flasks.

  that has been filtered beforehand and freeze-dried.

  By using the mixed anhydride of trans-diamino-1,2-cyclohexanetetracetic acid (CDTA) a solution of the corresponding complex is analogously obtained.

  of gadolinium-III of the CDTA-antibody conjugate.

  By using the manganese-II complex of ethylene-diaminetetraacetic acid, the manganese-II complexes of the DTPA-antibody conjugates are likewise obtained.

and CDTA-antibodies.

EXAMPLE 56

  Preparation of a solution of the gadolinium-III complex of the conjugate formed by 1-phenylethylenediaminetetraacetic acid with immunoglobulin. Following the procedure described in J. Med. Chem. 1974, Vol. 17, page 1307, cooled to +4 ° C.

  a 2% solution of the protein in a solution of 0.12

  sodium hydrogencarbonate, which contains 0.01 moles of ethylene-diamine-tetracetic acid, and

  a proportion, equivalent to that of the protein, of a solution

  freshly prepared and cooled by ice,

  of a diazonium salt of (4-amino-phenyl) -1-ethylene-

  diamine tetraacetic acid. It is stirred overnight at +4 ° C. (pH 8.1) and then dialyzed against a 0.1 molar solution of sodium citrate. When the dialysis is complete, an excess of gadolinium-III chloride is added to the solution of the conjugate.

  and ultrafiltration is performed to remove the ions.

  Finally, the solution is introduced into multidose vials after filtering it under conditions of sterility and

it is lyophilized.

EXAMPLE 57

  Preparation of a colloidal dispersion of a

Mn-CDTA-lipid conjugate.

  0.1 mmol of distearoyl phosphatidylethanolamine is stirred at room temperature for 24 hours.

  and 0.1 mmol of the bis-anhydride of the 1,2-diamino cyclo

  hexane-tetracetic trans in 50 ml of water. 0.1 mmol of manganese carbonate II is added and stirred again

  for 6 hours at room temperature. After purification

  on a solonne of Sephadex G50 the solubility

  in multidose vials by filtering it into

  sterility conditions, and freeze-dried.

  By operating in a similar manner, with gadolinium-III oxide, a colloidal dispersion of

gadolinium-DTPA-lipid conjugate.

EXAMPLE 58

  Preparation of liposomes loaded with gadolinium

  DTPA. By the procedure described in Proc. Natl. Acad. Sci. U.S.A. 75, 4194, a lipid mixture consisting of 75 mol%

  phosphatidyl choline and 25% of cholesterol

  500 mg of this mixture are dissolved in 30 ml of diethyl ether and, in an ultrasonic bath, 3 ml of a 0.1 molar solution of the N-di-salt are added dropwise to the solution obtained. methyl-glucamine of the gadolinium-III complex of the acid

  diethylene triamine pentacetic in water for injection.

  After the end of the addition of the solution the treatment is continued.

  Ultrasound for another 10 minutes, then concentrate

  on the rotary evaporator. The gelatinous residue is

  In a 0.125 molar solution of sodium chloride, the fractions of the contrast agent which have not been encapsulated are removed by carrying out several successive centrifugations at 0 ° C. (20 000 g / 20 minutes).

  obtained are then lyophilized in multidose vials.

  For the application the product is put in the form of a colloidal dispersion in a solution of sodium chloride

to 0.9% by weight.

Claims (14)

  1. Diagnostic agent usable for diagnosis   by NMR, characterized in that it comprises: (i) a physiologically acceptable, non-radioactive complex salt of the general formula I X-CH CH -X 2 \ / 2 (I) NOPE / \ V-CHR1 CHR V   in which X represents the radicals -COOY, -PO3HY or -CONHOY in   Y is a hydrogen atom, an equiva-   ionic metal ion, said metal being selected from elements having atomic numbers 21 to 29, 42, 44 and 58 to 70, or an acceptable cation. physiologically, a mineral or organic base or an amino acid, R1 represents in each case a hydrogen atom or a methyl group, and wherein either a) A represents the group -CHR2CHR3-, - CH2-CH2- (ZCH2-CH2) m -, N (CH2X) 2 CH2-CH2-N (CH2X) 2 or -CH 2 -CH-CH 2 -CH 2 CH 2 -N-CH 2 -CH 2   wherein X has the meanings given above, R and R together represent a trimethylene group or a tetramethylene group, or a tetramethylene group,   where each (in represents a hydrogen atom, a radi-   alkyl cal having up to 6 carbon atoms, a phenyl radical or a benzyl radical, m represents a number equal to 1 to 2 or to 3 and Z represents an oxygen or sulfur atom or the group NCH2X or NCH2CH 20R4 2 2 2 4   wherein X has the meanings given above and R4 represents an alkyl radical containing up to 6 carbon atoms, and each V has the same meaning as X or represents the group-CH20H or -COB, wherein B represents a radical of protein or lipid or NH (CH2) nX radical, wherein X has the meanings given above and n represents an integer of 1 to 12, with the proviso that at least one of the symbols V represents a group -COB as defined above,   and at least two of the Y substituents are equivalents   ionic valents of metals selected from atomic number elements 21 to 29, 42, 44, and 58 to 70, or   h) A represents the group -CHR2-CHR3-   in which R2 represents a hydrogen atom and R3 represents the group (CH2) p -C6H4-W-protein in which p is equal to 0 or 1, W represents -NN-, -NHCOCH2- or -NHCS-   and protein represents a protein radical, and V has the same meaning as X or represents the group -CH 2 OH, with the proviso that at least two of the Y substituents are ionic equivalents of metals selected from atomic number elements. at 29, 42, 44 and 58 to 70, and   (ii) a physically acceptable aqueous vehicle   logic. 2. Diagnostic agent according to claim 1 characterized in that the complex salt is present in a   concentration of 1 μmol to 1 mole per liter.   3. Diagnostic agent according to claim 1 or 2, characterized in that the complex salt is derived   diethylenetriaminepentacetic acid.   4. Diagnostic agent according to claim 1 or 2, characterized in that the complex salt is derived from   ethylenediamine tetracetic acid.   5. Diagnostic agent according to claim 1 or 2, characterized in that the complex salt is derived from cyclohexylene-1,2-diaminetetracetic-trans acid, or dioxo-13,23 tris- (carboxymethyl) 15,18 diacid, 21   pentaaza-12,15,18,21,24 pentatriacontanoic.   6. Diagnostic agent according to any one of   Claims 1 to 5, characterized in that the complex salt   is derived from a complexing agent bound as a conjugate with a biomolecule.   7. Diagnostic agent according to claim 6, characterized in that the biomolecule is a lipid or a protein.   8. Diagnostic agent according to claim 7, characterized in that the protein is insulin, a   albumin or a monoclonal antibody.   9. Diagnostic Aqcnt according to Claim 8   characterized in that the monoclonal antibody is specific   that antigens associated with tumors.   10. Diagnostic agent according to any one of   Claims I to 5 characterized in that the complex salt   is derived from a complexing acid forming a conjugate   or an inclusion compound with a liposome.   11. Diagnostic agent according to claim 1 or 2, characterized in that the complex salt is chosen from the group consisting of: N-methylglucamine di-salt of the gadolinium-III complex of dioxo 13, 23 tris- (carboxymethyl) -15,18,21 penta-aza-12,15,18,21,24 pentatriacontanediol, the gadolinium-III complex of the conjugate formed by   Diethylene triamine pentaacetic acid with   globulin, the gadolinium-III complex of the conjugate formed by diethylene triamine pentacetic acid with human serum albumin, the gadolinium-III complex of the conjugate formed by the acid   Diethylene triamine pentacetic with a monoclonal antibody   clonal, the complex of manganese-II conjugate formed by the acid   1,2-diamino-tetraacetic-trans-cyclohexylene with an anti-   monoclonal body, the manganese-II complex of a cyclohexylene-1,1,2 diamine-tetracetic-trans acid lipid conjugate, the gadolinium-III complex of an inclusion compound of diethylene-triaminepentacetic acid with a liposome, the disodium salt of the dioxo], 3-tris (carboxymethyl) -15,18,21 penta-aza-12, 15   Li.? L. 24 pentatridaontadne-dioic.   12. Diagnostic agent according to any one of   claims 1 to 11, characterized in that it is under a   Dosage form suitable for oral administration or intravascular.   i0484 4 o8 I 3. I) I) I) I) I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I   diagnostic device according to any one of claims I to 11.   14. Process for preparing a diagnostic agent   any one of claims 1 to 11,   characterized in that the complex salt, dissolved or suspended in water or in physiological saline, is put, with additives taken from those normally used in pharmacy, in a form which is suitable for   intravascular or oral application.   15. Non-radioactive complex salt, physiologically acceptable, characterized in that it corresponds to the general formula I X -CH2 CH2 -X NOPE V-CHR 1 (I) CHR 1-V   in which the different substituents have the given meanings in claim 1.   16. Complex salt according to claim 15, characterized   terized in that it contains more than two radicals   represented by X and in which at least one of the substitutes   Y is a physiologically acceptable cation.   logic of an organic base or an amino acid.